Villegas was born in Medellín, Colombia, and took up golf as a child. After several different National Junior Championships in Colombia between the ages of 8 and 15, at 16 he became the first player in Colombian golf history to win the Amateur's Grand Slam in the same year: The National Junior Championship (stroke play), the National Junior Championship (match play), the National Amateur Championship, and the Colombian Open in the amateur category. Then, in 2001, he became only the second player to win the Colombian Open as an amateur. His success in Colombian golf throughout the 1990s earned him the distinction of "Player of the Decade" issued by the Colombian Golf Federation.

Villegas began playing on the PGA Tour in 2004 and earned his PGA Tour card just prior to the 2006 season. He had a blistering start to his 2006 rookie year on tour, with two second-place finishes and a third place (at The Players Championship) in his first nine events. He missed making the 2006 Masters Tournament in his rookie year by a single position on the Official PGA Tour Money List (11th). However, he made his first Masters' appearance in 2007 by finishing in the top 40 of the Official PGA Tour Money List for 2006. He qualified for the 2008 Masters through his exceptional play during the inaugural FedEx Cup playoff system, that included an opening round 63 (8 under par) at the Deutsche Bank Championship and three straight top 10 finishes. He entered the FedEx Cup playoffs in 52nd place and improved to 28th place through his play in the first three events, thus qualifying for the 30-man field at The Tour Championship in Atlanta, Georgia, where he finished in the top 10 for the third straight week and finished 24th on the FedEx Cup points list.

Villegas won his second professional event at the Coca-Cola Tokai Classic on the Japan Golf Tour in September 2007. By doing so, he earned ¥24,000,000 (approximately US$208,272). He shot a score of 282 (−2) and defeated Toyokazu Fujishima in a playoff by draining a 20-foot putt on the winning hole. In 2006 Camilo signed an endorsement deal with Red Bull, and has represented the energy drink company since then as their sole PGA Tour golf athlete. Villegas won his third professional event at the TELUS Skins Game in June 2008 where he defeated a field that included Greg Norman, Colin Montgomerie, Mike Weir and "Mr. Skins", Fred Couples. Villegas took six skins for $130,000 with a short birdie putt on the 14th hole, and then won an additional four skins for $100,000 in a playoff, which was decided with a closest-to-the-pin shootout from 130 yards out on the 18th hole.

Villegas recorded a record-breaking second round in the 2008 Open Championship. He shot 65, which was the lowest score for any Open Championship second round at Royal Birkdale. He started off with two bogeys but ended with five consecutive birdies which put him at 5 under for his round. Villegas won his first PGA Tour title in September 2008, winning the BMW Championship by two shots over Dudley Hart. For the last 44 holes of the tournament, Villegas did not three putt, one-putting 27 of those last 44 holes. This victory took him to a career high of 18th in the Official World Golf Rankings.[3]

Villegas followed his BMW Championship win with a victory in The Tour Championship. He beat Sergio García in a playoff, having trailed by five shots going into the final round. The win took Villegas to number seven in the Official World Golf Rankings[4] and established him as the highest ranked golfer from South America. He finished the season 7th on the PGA Tour money list.

In late 2008 Villegas joined the European Tour, making his first European Tour appearance at the 2008 HSBC Champions, the first tournament of the 2009 season. However he will continue to play predominately in the United States. He had no victories in 2009 but had five top-10 finishes and ended the season ranked 45th on the PGA Tour money list and in the top 30 of the European Tour's Race to Dubai.

He spent over 30 weeks in the top-10 of the Official World Golf Rankings since 2008, with a career high rank of seventh.[5]

In March 2010, Villegas earned his third victory on the PGA Tour, winning The Honda Classic by five strokes over Anthony Kim.[7] He chose not to maintain his status on the European Tour, and a slump in form in 2012 meant he had to enter the PGA Tour's Qualifying School at the end of the season; he finished 144th on the money list. Villegas did not regain a Tour Card but had conditional status on the PGA Tour for 2013, playing in the 126-150 category. His status gave him entry based on sponsor exemptions, past championships, and priority ranking. He regained full privileges for 2014 with a 110th-place finish in the FedEx Cup. In 2014, Villegas won the Wyndham Championship, his first win on Tour in more than four years. The win moved him into the 37th position of the 2014 FedEX Cup prior to going into the FedEx Cup playoffs. With this victory, Villegas earns an invitation into the 2015 Masters Tournament and two years full-exempt status on the PGA Tour.

In July 2016, Villegas withdrew from the Olympics in Rio to concentrate in the PGA Tour and secure a card for the 2016–17 season. He also mentioned concerns over the Zika virus as another reason to pull out from the Olympics.[8] Villegas did not regain his Tour card and is playing the 2016–17 season with only past champion status.

Throughout the PGA Tour and among the media, there is a debate over how Villegas's name should be pronounced.

In Spanish, Villegas is pronounced "bee-YAY-gahss" or "bee-JAY-gahss."[9] The official language in Colombia is Spanish. For more on the ambiguity of this pronunciation, see Yeísmo.

Recent examples from discussion forums, television coverage and sports articles—including interviews with Villegas himself—have supported the standard pronunciation of "bee-JAY-gahss" for his last name, although there are some who have not yet adopted the proper first name pronunciation, "kah-MEE-lo."[10]

Villegas is often compared with Spider-Man for his unique style of reading greens before he putts.

^At the "English Pronunciation Guide to the Names of People, Places, and Stuff"- inogolo – you can actually hear the correct pronunciation in Spanish, for yourself, as well as for Camilo (notice the single "l").